Latency-Associated Viral Interleukin-10 (IL-10) Encoded by Human Cytomegalovirus Modulates Cellular IL-10 and CCL8 Secretion during Latent Infection through Changes in the Cellular MicroRNA hsa-miR-92a

Abstract

The UL111A gene of human cytomegalovirus encodes a viral homologue of the cellular immunomodulatory cytokine interleukin 10 (cIL-10), which, due to alternative splicing, results in expression of two isoforms designated LAcmvIL-10 (expressed during both lytic and latent infection) and cmvIL-10 (identified only during lytic infection). We have analyzed the functions of LAcmvIL-10 during latent infection of primary myeloid progenitor cells and found that LAcmvIL-10 is responsible, at least in part, for the known increase in secretion of cellular IL-10 and CCL8 in the secretomes of latently infected cells. This latency-associated increase in CCL8 expression results from a concomitant LAcmvIL-10-mediated suppression of the expression of the cellular microRNA (miRNA) hsa-miR-92a, which targets CCL8 directly. Taking the data together, we show that the previously observed downregulation of hsa-miR-92a and upregulation of CCL8 during HCMV latent infection of myeloid cells are intimately linked via the latency-associated expression of LAcmvIL-10.IMPORTANCE HCMV latency causes significant morbidity and mortality in immunocompromised individuals, yet HCMV is carried silently (latently) in 50 to 90% of the population. Understanding how HCMV maintains infection for the lifetime of an infected individual is critical for the treatment of immunocompromised individuals suffering with disease as a result of HCMV. In this study, we analyze one of the proteins that are expressed during the “latent” phase of HCMV, LAcmvIL-10, and find that the expression of the gene modulates the microenvironment of the infected cell, leading to evasion of the immune system.

High-Throughput Analysis of Human Cytomegalovirus Genome Diversity Highlights the Widespread Occurrence of Gene-Disrupting Mutations and Pervasive Recombination

“…In this regard, cmvIL-10 has been shown to impair cytotrophoblast remodeling of the uterine vasculature, thereby possibly enhancing congenital disease (118). The latency-associated LAcmvIL-10 product cannot signal through human IL-10 receptors in the same fashion but was recently shown to upregulate the expression of cellular IL-10 and CCL8 (119). Another mutated gene with potential implications for the immunomodulatory capacities of isolates is UL40.…”

Latent human cytomegalovirus enhances HIV-1 infection in CD34+ progenitor cells

“…These latencyassociated genes include UL111.5A, LUNA, and UL138 and can regulate host cell responses, such as downregulating major histocompatibility complex (MHC) class II molecules, while inducing host interleukin-10 (IL-10), chemokine (C-C motif) ligand 8 (CCL8), and the multidrug resistance-associated protein-1 (MRP1). [3][4][5][6][7][8] These HCMV latent genes are important for facilitating establishment/maintenance of latency in which host cell mechanisms are modulated. However, only few latent genes have known functions.…”

Human Cytomegalovirus US28 Is Important for Latent Infection of Hematopoietic Progenitor Cells

“…For example, viral proteins including UL138 (29,30), pp71 (13), LUNA (31), UL144 (32), and viral interleukin-10 (latency-associated HCMV ho-molog of IL-10 [LAcmvIL-10]) (33)(34)(35)(36) contribute to successful latency and reactivation in culture. HCMV has co-opted cellular factors as well, such as cellular microRNAs (miRNAs) (36)(37)(38), transcription factors (32,38), and cell signaling (38,39). It is clear that HCMV latency and reactivation are multifaceted processes and thus likely that our full understanding of these stages of infection remains incomplete.…”